Bioinformatic perspectives on NRPS/PKS megasynthases: Advances and challenges

The increased understanding of both fundamental principles and mechanistic variations of NRPS/PKS megasynthases along with the unprecedented availability of microbial genome sequences has inspired a number of in silico studies of both enzyme families. The insights that can be extracted from these analyses go far beyond a rough classification of data and have turned bioinformatics into a frontier field of natural products research. As databases are flooded with NRPS/PKS gene sequences of microbial genomes and metagenomes, increasingly reliable structural prediction methods can help to uncover hidden treasures. Already, phylogenetic analyses have revealed that NRPS/PKS pathways should not simply be regarded as enzyme complexes, specifically evolved to produce a selected natural product. Rather, they represent a collection of genetic options, allowing biosynthetic pathways to be shuffled in a process of perpetual chemical innovation. Understanding the principles underlying domain specificities, protein-protein interactions and pathway diversification in nature can give impulses for genomic mining approaches and genetic engineering of libraries of novel peptides and polyketides. The successful translation of the knowledge obtained from bioinformatic dissection of NRPS/PKS megasynthases into new techniques for drug discovery and design remain challenges for the future.